Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia. Fibromyalgia is frequently comorbid with psychiatric conditions such as depression, anxiety, and stress-related disorders. Currently, there is no cure for fibromyalgia. Medical therapies with anti-depressants have demonstrated the ability to reduce symptoms. Milnacipran is a cyclopropylamide and a selective norepinephrine and serotonin reuptake inhibitor (SNRI) approved by the FDA for the management of fibromyalgia. A significant percentage of patients discontinue taking milnacipran due to adverse events such as nausea, palpitations, depression, increased heart rate, constipation, and headaches. Other adverse events reported when taking milnacipran include increases in heart rate and blood pressure, serotonin syndrome, seizures, hepatotoxicity, hyponatremia, abnormal bleeding, activation of mania and dysuria. Thus, there is a need to identify improved therapies.
Bonnarud et al., J Med Chem, 1987, 30, 318-325 disclose cyclopropane carbocylic acid derivatives. See also U.S. Pat. No. 4,567,288 and U.S. Published Application No. 2008/0051604. The authors report uses as antidepressants and for the treatment of pain. Certain cyclopropyl derivatives are also disclosed in Davies & Denton, Chem. Soc. Rev., 2009, 38, 3061-3071; Pelphrey et al., Chem. Sci., 2010, 1, 254-257, Davies et al., Tetrahedron Letters, (1996) 37(24), 4133-4136, Denton & Davies, Organic Letters, (2009) 11(4), 787-790. See also U.S. Pat. No. 7,385,064.